In view of higher incidence of neoplasia in the elderly, alterations in the Natural Killer (NK) cell system will be studied in healthy humans with special reference to aging. We proposed to critically examine why the NK system is hyperactive(as we have found) in a majority of healthy elderly (greater than 80 years) despite a decline in T&B cell reactivities. If IL-2 deficiency is responsible for their T cell defects, how do the NK cells escape? It is our premise that ultimate changes in cellular factors (NK effector and progenitor frequency) and/or humoral factors (lymphokines) may be responsible for these alterations. To achieve this goal, we will enumerate NK subsets (co-expression of CD2, CD8,CD11a,CD11b,&CD18 with major NK markers Leu-19,CD16, and Leu-7) and determine their contribution to the total cytolytic potential of NK cells. Plasma levels and capacity of lymphocytes to secrete IL-2 and interferon-gamma will be measured. Changes in sensitivity to recombinant human alpha and gamma IFNs (activation of NK cells and anti-proliferative effect on T cells) and sensitivity to down-regulation by recombinant IL-4 of IL-2 augmented NK activity will be assessed. Evidence for the existence of pre-activated NK cells will be sought (coexpression of CD25, HLA-DR and Transferin Receptor with Leu-19/CD16+). LDA will be performed on lymphocytes, NK and T cells with recombinant human IL-2 We will investigate if there is a senescence-related shift in NK progenitor (cytotoxic & Proliferative) frequency, performance level, oncolytic potential, affinity to sensitive/insensitive tumors and the major LAK precursor & effector phenotypes. We will resolve if there are intrinsic Immunosenescent features that distinguish the NK system in the aged is attributable to a deletion of a low-NK younger adult population. We will explore if the NK system in the elderly is familial. The results may provide a rationals for immunopharmacological interventions, basal reference values for clinical/basic studies in aging humans, a longevity- related predictive value and NK cell clones from young/old donors for future molecular investigations.